Degradation of Perineuronal Nets in the Ventral Hippocampus of Adult Rats Recreates an Adolescent-Like Phenotype of Stress Susceptibility.

Background: Psychiatric disorders often emerge during late adolescence/early adulthood, a period with increased susceptibility to socioenvironmental factors that coincides with incomplete parvalbumin interneuron (PVI) development. Stress during this period causes functional loss of PVIs in the ventral hippocampus (vHip), which has been associated with dopamine system overdrive. This vulnerability persists until the appearance of perineuronal nets (PNNs) around PVIs. We assessed the long-lasting effects of adolescent or adult stress on behavior, ventral tegmental area dopamine neuron activity, and the number of PVIs and their associated PNNs in the vHip. Additionally, we tested whether PNN removal in the vHip of adult rats, proposed to reset PVIs to a juvenile-like state, would recreate an adolescent-like phenotype of stress susceptibility. Methods: Male rats underwent a 10-day stress protocol during adolescence or adulthood. Three to 4 weeks poststress, we evaluated behaviors related to anxiety, sociability, and cognition, ventral tegmental area dopamine neuron activity, and the number of PV+ and PNN+ cells in the vHip. Furthermore, adult animals received intra-vHip infusion of ChABC (chondroitinase ABC) to degrade PNNs before undergoing stress. Results: Unlike adult stress, adolescent stress induced anxiety responses, reduced sociability, cognitive deficits, ventral tegmental area dopamine system overdrive, and decreased PV+ and PNN+ cells in the vHip. However, intra-vHip ChABC infusion caused the adult stress to produce changes similar to the ones observed after adolescent stress. Conclusions: Our findings underscore adolescence as a period of heightened vulnerability to the long-lasting impact of stress and highlight the protective role of PNNs against stress-induced damage in PVIs.

In this work, we aimed to go deeper into understanding perineuronal nets (PNNs), a specialized extracellular matrix that evolves and protects inhibitory neurons in the brain, specifically parvalbumin-positive interneurons (PVIs). PVIs are essential in regulating brain activity. PNNs only reach maturity in adulthood, which leaves these interneurons unprotected during early life. To investigate this vulnerability, we conducted experiments in which we exposed adolescent and adult animals to a stress protocol. We observed that adolescent animals exhibited a higher susceptibility to developing changes associated with psychiatric disorders later in life. This susceptibility may stem from the absence of PNN protection around their PVIs. To explore this possibility further, we administered an enzyme into a specific brain region, the ventral hippocampus, of adult animals to selectively remove PNNs and induce an adolescent-like state. When subjected to stress, these animals displayed abnormalities similar to those observed in animals stressed during adolescence. Our findings have significant implications, suggesting that the presence of PNN protection around PVIs may be critical for mitigating stress-related psychiatric disorders.

Formal Radiologist Interpretations of Intraoperative Spine Radiographs Have Low Clinical Value.

STUDY DESIGN: Retrospective cohort. OBJECTIVE: To evaluate the clinical relevance, usefulness, and financial implications of intraoperative radiograph interpretation by radiologists in spine surgery. SUMMARY OF BACKGROUND DATA: Due to rising health care costs, spine surgery is under scrutiny to maximize value-based care. Formal radiographic analysis remains a potential source of unnecessary health care costs, especially for intraoperative radiographs. MATERIALS AND METHODS: A retrospective cohort analysis was performed on all adult elective spine surgeries at a single institution between July 2020 and July 2021. Demographic and radiographic data were collected, including intraoperative localization and post-instrumentation radiographs. Financial data were obtained through the institution's price estimator. Radiographic characteristics included time from radiographic imaging to completion of radiologist interpretation report, completion of radiologist interpretation report before the conclusion of surgical procedure, clinical relevance, and clinical usefulness. Reports were considered clinically relevant if the spinal level of the procedure was described and clinically useful if completed before the conclusion of the procedure and deemed clinically relevant. RESULTS: Four hundred eighty-one intraoperative localization and post-instrumentation radiographs from 360 patients revealed a median delay of 128 minutes between imaging and completion of the interpretive report. Only 38.9% of reports were completed before the conclusion of surgery. There were 79.4% deemed clinically relevant and only 33.5% were clinically useful. Localization reports were completed more frequently before the conclusion of surgery (67.2% vs. 34.4%) but with lower clinical relevance (90.1% vs. 98.5%) and clinical usefulness (60.3% vs. 33.6%) than post-instrumentation reports. Each patient was charged $32 to $34 for the interpretation fee, cumulating a minimum total cost of $15,392. CONCLUSIONS: Formal radiographic interpretation of intraoperative spine radiographs was of low clinical utility for spine surgeons. Institutions should consider optimizing radiology workflows to improve timeliness and clinical relevance or evaluate the necessity of reflexive consultation to radiology for intraoperative imaging interpretation to ensure that value-based care is maximized during spine surgeries. LEVEL OF EVIDENCE: 3.

The Effects of Cervical Orthoses on Head and Intervertebral Range of Motion.

STUDY DESIGN: Prospective Cohort. OBJECTIVE: Quantify and compare the effectiveness of cervical orthoses in restricting intervertebral kinematics during multiplanar motions. SUMMARY OF BACKGROUND DATA: Previous studies evaluating the efficacy of cervical orthoses measured global head motion and did not evaluate individual cervical motion segment mobility. Prior studies focused only on the flexion/extension motion. METHODS: Twenty adults without neck pain participated. Vertebral motion from the occiput through T1 was imaged using dynamic biplane radiography. Intervertebral motion was measured using an automated registration process with validated accuracy better than 1 degree. Participants performed independent trials of maximal flexion/extension, axial rotation, and lateral bending in a randomized order of unbraced, soft collar (foam), hard collar (Aspen), and cervical thoracic orthosis (CTO) (Aspen) conditions. Repeated-measures ANOVA was used to identify differences in the range of motion (ROM) among brace conditions for each motion. RESULTS: Compared with no collar, the soft collar reduced flexion/extension ROM from occiput/C1 through C4/C5, and reduced axial rotation ROM at C1/C2 and from C3/C4 through C5/C6. The soft collar did not reduce motion at any motion segment during lateral bending. Compared with the soft collar, the hard collar reduced intervertebral motion at every motion segment during all motions, except for occiput/C1 during axial rotation and C1/C2 during lateral bending. The CTO reduced motion compared with the hard collar only at C6/C7 during flexion/extension and lateral bending. CONCLUSIONS: The soft collar was ineffective as a restraint to intervertebral motion during lateral bending, but it did reduce intervertebral motion during flexion/extension and axial rotation. The hard collar reduced intervertebral motion compared with the soft collar across all motion directions. The CTO provided a minimal reduction in intervertebral motion compared with the hard collar. The utility in using a CTO rather than a hard collar is questionable, given the cost and little or no additional motion restriction.

Transgene-induced cell death following dengue-2 virus infection in Aedes aegypti.

Dengue viruses (DENVs) are mosquito-borne flaviviruses causing millions of human infections each year and pose a challenge for public health systems worldwide. Aedes aegypti is the principal vector species transmitting DENVs to humans. Controlling Ae. aegypti is difficult due to the abundance of breeding sites and increasing insecticide resistance in the vector populations. Developing new vector control strategies is critical for decreasing the disease burden. One potential approach is genetically replacing Ae. aegypti populations with vector populations highly resistant to DENV transmission. Here, we focus on an alternative strategy for generating dengue 2 virus (DENV-2) resistance in genetically-modified Ae. aegypti in which the mosquitoes express an inactive form of Michelob_x (Mx), an antagonist of the Inhibitor of Apoptosis (IAP), to induce apoptosis in those cells in which actively replicating DENV-2 is present. The inactive form of Mx was flanked by the RRRRSAG cleavage motif, which was recognized by the NS2B/NS3 protease of the infecting DENV-2 thereby releasing and activating Mx which then induced apoptosis. Our transgenic strain exhibited a significantly higher mortality rate than the non-transgenic control when infected with DENV-2. We also transfected a DNA construct containing inactive Mx fused to eGFP into C6/36 mosquito cells and indirectly observed Mx activation on days 3 and 6 post-DENV-2 infections. There were clear signs that the viral NS2B/NS3 protease cleaved the transgene, thereby releasing Mx protein into the cytoplasm, as was confirmed by the detection of eGFP expression in infected cells. The present study represents proof of the concept that virus infection can be used to induce apoptosis in infected mosquito cells.

Levetiracetam Attenuates Adolescent Stress-induced Behavioral and Electrophysiological Changes Associated With Schizophrenia in Adult Rats.

BACKGROUND AND HYPOTHESIS: Stress during adolescence is a major risk factor for schizophrenia. We have found previously in rats that adolescent stress caused, in adulthood, behavioral changes and enhanced ventral tegmental area (VTA) dopamine system activity, which were associated with dysregulation of the excitatory-inhibitory (E/I) balance in the ventral hippocampus (vHip). Levetiracetam, an anticonvulsant drug, regulates the release of neurotransmitters, including glutamate, via SV2A inhibition. It also modulates parvalbumin interneuron activity via Kv3.1 channels. Therefore, levetiracetam could ameliorate deficits in the E/I balance. We tested whether levetiracetam attenuate the adolescent stress-induced behavioral changes, vHip hyperactivity, and enhanced VTA dopamine system activity in adult rats. STUDY DESIGN: Male Sprague-Dawley rats were subjected to a combination of daily footshock (postnatal day [PD] 31-40), and three 1 h-restraint stress sessions (at PD31, 32, and 40). In adulthood (PD62), animals were tested for anxiety responses (elevated plus-maze and light-dark box), social interaction, and cognitive function (novel object recognition test). The activity of vHip pyramidal neurons and VTA dopamine neurons was also recorded. STUDY RESULTS: Adolescent stress produced anxiety-like responses and impaired sociability and cognitive function. Levetiracetam (10 mg/kg) reversed these changes. Levetiracetam also reversed the increased VTA dopamine neuron population activity and the enhanced firing rate of vHip pyramidal neurons induced by adolescent stress. CONCLUSIONS: These findings suggest that levetiracetam attenuates the adverse outcomes associated with schizophrenia caused by stress during adolescence.

Inequalities in the prevalence of cardiovascular disease risk factors in Brazilian slum populations: A cross-sectional study.

BACKGROUND: Social and environmental risk factors in informal settlements and slums may contribute to increased risk of cardiovascular disease (CVD). This study assesses the socioeconomic inequalities in CVD risk factors in Brazil comparing slum and non-slum populations. METHODS: Responses from 94,114 individuals from the 2019 Brazilian National Health Survey were analysed. The United Nations Human Settlements Programme definition of a slum was used to identify slum inhabitants. Six behavioural risk factors, four metabolic risk factors and doctor-diagnosed CVD were analysed using Poisson regression models adjusting for socioeconomic characteristics. RESULTS: Compared to urban non-slum inhabitants, slum inhabitants were more likely to: have low (less than five days per week) consumption of fruits (APR: 1.04, 95%CI 1.01-1.07) or vegetables (APR: 1.08, 95%CI 1.05-1.12); drink four or more alcoholic drinks per day (APR: 1.05, 95%CI 1.03-1.06); and be physically active less than 150 minutes per week (APR: 1.03, 95%CI 1.01-1.04). There were no differences in the likelihoods of doctor-diagnosed metabolic risk factors or CVD between the two groups in adjusted models. There was a higher likelihood of behavioural and metabolic risk factors among those with lower education, with lower incomes, and the non-White population. CONCLUSIONS: Brazilians living in slums are at higher risk of behavioural risk factors for CVD, suggesting local environments might impact access to and uptake of healthy behaviours.

Inequalities in the prevalence of major depressive disorder in Brazilian slum populations: a cross-sectional analysis.

AIMS: The mental health of slum residents is under-researched globally, and depression is a significant source of worldwide morbidity. Brazil's large slum-dwelling population is often considered part of a general urban-poor demographic. This study aims to identify the prevalence and distribution of depression in Brazil and compare mental health inequalities between slum and non-slum populations. METHODS: Data were obtained from Brazil's 2019 National Health Survey. Slum residence was defined based on the UN-Habitat definition for slums and estimated from survey responses. Doctor-diagnosed depression, Patient Health Questionnaire (PHQ-9)-screened depression and presence of undiagnosed depression (PHQ-9-screened depression in the absence of a doctor's diagnosis) were analysed as primary outcomes, alongside depressive symptom severity as a secondary outcome. Prevalence estimates for all outcomes were calculated. Multivariable logistic regression models were used to investigate the association of socioeconomic characteristics, including slum residence, with primary outcomes. Depressive symptom severity was analysed using generalised ordinal logistic regression. RESULTS: Nationally, the prevalence of doctor diagnosed, PHQ-9 screened and undiagnosed depression were 9.9% (95% confidence interval (CI): 9.5-10.3), 10.8% (95% CI: 10.4-11.2) and 6.9% (95% CI: 6.6-7.2), respectively. Slum residents exhibited lower levels of doctor-diagnosed depression than non-slum urban residents (8.6%; 95% CI: 7.9-9.3 v. 10.7%; 95% CI: 10.2-11.2), while reporting similar levels of PHQ-9-screened depression (11.3%; 95% CI: 10.4-12.1 v. 11.3%; 95% CI: 10.8-11.8). In adjusted regression models, slum residence was associated with a lower likelihood of doctor diagnosed (adjusted odds ratio (adjusted OR): 0.87; 95% CI: 0.77-0.97) and PHQ-9-screened depression (adjusted OR: 0.87; 95% CI: 0.78-0.97). Slum residents showed a greater likelihood of reporting less severe depressive symptoms. There were significant ethnic/racial disparities in the likelihood of reporting doctor-diagnosed depression. Black individuals were less likely to report doctor-diagnosed depression (adjusted OR: 0.66; 95% CI: 0.57-0.75) than white individuals. A similar pattern was observed in Mixed Black (adjusted OR: 0.72; 95% CI: 0.66-0.79) and other (adjusted OR: 0.63; 95% CI: 0.45-0.88) ethnic/racial groups. Slum residents self-reporting a diagnosis of one or more chronic non-communicable diseases had greater odds of exhibiting all three primary depression outcomes. CONCLUSIONS: Substantial inequalities characterise the distribution of depression in Brazil including in slum settings. People living in slums may have lower diagnosed rates of depression than non-slum urban residents. Understanding the mechanisms behind the discrepancy in depression diagnosis between slum and non-slum populations is important to inform health policy in Brazil, including in addressing potential gaps in access to mental healthcare.

Beyond Dopamine Receptor Antagonism: New Targets for Schizophrenia Treatment and Prevention.

Treatment of schizophrenia (SCZ) historically relies on the use of antipsychotic drugs to treat psychosis, with all of the currently available antipsychotics acting through the antagonism of dopamine D2 receptors. Although antipsychotics reduce psychotic symptoms in many patients, they induce numerous undesirable effects and are not effective against negative and cognitive symptoms. These highlight the need to develop new drugs to treat SCZ. An advanced understanding of the circuitry of SCZ has pointed to pathological origins in the excitation/inhibition balance in regions such as the hippocampus, and restoring function in this region, particularly as a means to compensate for parvalbumin (PV) interneuron loss and resultant hippocampal hyperactivity, may be a more efficacious approach to relieve a broad range of SCZ symptoms. Other targets, such as cholinergic receptors and the trace amine-associated receptor 1 (TAAR1), have also shown some promise for the treatment of SCZ. Importantly, assessing efficacy of novel compounds must take into consideration treatment history of the patient, as preclinical studies suggest prior antipsychotic treatment may interfere with the efficacy of these novel agents. However, while novel therapeutic targets may be more effective in treating SCZ, a more effective approach would be to prevent the transition to SCZ in susceptible individuals. A focus on stress, which has been shown to be a predisposing factor in risk for SCZ, is a possible avenue that has shown promise in preclinical studies. Therefore, therapeutic approaches based on our current understanding of the circuitry of SCZ and its etiology are likely to enable development of more effective therapeutic interventions for this complex disorder.

Peripubertal mGluR2/3 Agonist Treatment Prevents Hippocampal Dysfunction and Dopamine System Hyperactivity in Adulthood in MAM Model of Schizophrenia.

Pomaglumetad methionil (POM), a group 2 metabotropic glutamate receptor (mGluR2/3) agonist, showed promise as a novel antipsychotic in preclinical research but failed to show efficacy in clinical trials, though it has been suggested that it may be effective in certain patient populations, including early in disease patients. We used the methyazoxymethanol acetate (MAM) rat model of schizophrenia to determine whether POM may prevent the development of dopamine (DA) system dysfunction in a model representative of the hyperdopaminergic state thought to underlie psychosis, compared to control (SAL) rats. MAM and SAL rats were administered either POM (3 mg/kg, i.p.), vehicle (1 ml/kg), or no injection during postnatal day (PD) 31-40. In either late adolescence (PD 47-56) or adulthood (PD 83-96), novel object recognition (NOR) was tested, followed by anesthetized in vivo electrophysiological recordings of VTA DA neuron activity or ventral hippocampal (vHPC) pyramidal neuron activity. MAM rats treated with POM demonstrated increased NOR in adulthood compared to no injection MAM rats, but not compared to vehicle-treated MAM rats. POM-treated MAM rats demonstrated normalized DA neuron population activity and vHPC pyramidal neuron activity compared to vehicle and no injection MAM rats in both late adolescence and adulthood. No significant differences were observed across treatment groups in SAL rats. These results suggest that peripubertal mGluR2/3 agonist administration can prevent the emergence of vHPC pyramidal neuron hyperactivity and increased DA neuron population activity in adult MAM rats.

Adolescent Exposure to WIN 55212-2 Render the Nigrostriatal Dopaminergic Pathway Activated During Adulthood.

BACKGROUND: During adolescence, neuronal circuits exhibit plasticity in response to physiological changes and to adapt to environmental events. Nigrostriatal dopaminergic pathways are in constant flux during development. Evidence suggests a relationship between early use of cannabinoids and psychiatric disorders characterized by altered dopaminergic systems, such as schizophrenia and addiction. However, the impact of adolescent exposure to cannabinoids on nigrostriatal dopaminergic pathways in adulthood remains unclear. The aim of this research was to determine the effects of repeated activation of cannabinoid receptors during adolescence on dopaminergic activity of nigrostriatal pathways and the mechanisms underlying this impact during adulthood. METHODS: Male Sprague-Dawley rats were treated with 1.2 mg/kg WIN 55212-2 daily from postnatal day 40 to 65. Then no-net flux microdialysis of dopamine in the dorsolateral striatum, electrophysiological recording of dopaminergic neuronal activity, and microdialysis measures of gamma-aminobutyric acid (GABA) and glutamate in substantia nigra par compacta were carried out during adulthood (postnatal days 72-78). RESULTS: Repeated activation of cannabinoid receptors during adolescence increased the release of dopamine in dorsolateral striatum accompanied by increased population activity of dopamine neurons and decreased extracellular GABA levels in substantia nigra par compacta in adulthood. Furthermore, perfusion of bicuculline, a GABAa antagonist, into the ventral pallidum reversed the increased dopamine neuron population activity in substantia nigra par compacta induced by adolescent cannabinoid exposure. CONCLUSIONS: These results suggest that adolescent exposure to cannabinoid agonists produces disinhibition of nigrostriatal dopamine transmission during adulthood mediated by decreased GABAergic input from the ventral pallidum.

Nicotine Self-administration Is Not Increased in the Methylazoxymethanol Acetate Rodent Model of Schizophrenia.

INTRODUCTION: Patients with schizophrenia (SCZ) smoke at a rate of 4-5 times higher than the general population, contributing to negative health consequences in this group. One possible explanation for this increased smoking is that individuals with SCZ find nicotine (NIC) more reinforcing. However, data supporting this possibility are limited. METHODS: The present experiments examined self-administration of NIC, alone or in combination with other reinforcers, across a range of doses in the methylazoxymethanol acetate (MAM) rodent model of SCZ. RESULTS: MAM and control animals did not differ in NIC self-administration across a range of doses and schedules of reinforcement, in both standard 1-hour self-administration sessions and 23-hour extended access sessions. However, MAM animals responded less for sucrose or reinforcing visual stimuli alone or when paired with NIC. CONCLUSIONS: To the extent that MAM-treated rats are a valid model of SCZ, these results suggest that increased NIC reinforcement does not account for increased smoking in SCZ patients. IMPLICATIONS: This study is the first to utilize nicotine self-administration, the gold standard for studying nicotine reinforcement, in the methylazoxymethanol acetate model of schizophrenia, which is arguably the most comprehensive animal model of the disease currently available. Our assessment found no evidence of increased nicotine reinforcement in methylazoxymethanol acetate animals, suggesting that increased reinforcement may not perpetuate increased smoking in schizophrenia patients.

Smoke-free legislation and neonatal and infant mortality in Brazil: longitudinal quasi-experimental study.

OBJECTIVE: To examine the associations of partial and comprehensive smoke-free legislation with neonatal and infant mortality in Brazil using a quasi-experimental study design. DESIGN: Monthly longitudinal (panel) ecological study from January 2000 to December 2016. SETTING: All Brazilian municipalities (n=5565). PARTICIPANTS: Infant populations. INTERVENTION: Smoke-free legislation in effect in each municipality and month. Legislation was encoded as basic (allowing smoking areas), partial (segregated smoking rooms) or comprehensive (no smoking in public buildings). Associations were quantified by immediate step and longer term slope/trend changes in outcomes. STATISTICAL ANALYSES: Municipal-level linear fixed-effects regression models. MAIN OUTCOMES MEASURES: Infant and neonatal mortality. RESULTS: Implementation of partial smoke-free legislation was associated with a -3.3 % (95% CI -6.2% to -0.4%) step reduction in the municipal infant mortality rate, but no step change in neonatal mortality. Comprehensive smoke-free legislation implementation was associated with -5.2 % (95% CI -8.3% to -2.1%) and -3.4 % (95% CI -6.7% to -0.1%) step reductions in infant and neonatal mortality, respectively, and a -0.36 (95% CI -0.66 to-0.06) annual decline in the infant mortality rate. We estimated that had all smoke-free legislation introduced since 2004 been comprehensive, an additional 10 091 infant deaths (95% CI 1196 to 21 761) could have been averted. CONCLUSIONS: Strengthening smoke-free legislation in Brazil is associated with improvements in infant health outcomes-particularly under comprehensive legislation. Governments should accelerate implementation of comprehensive smoke-free legislation to protect infant health and achieve the United Nation's Sustainable Development Goal three.

Costs Associated with the Treatment of Low Back Disorders: A Comparison of Surgeons and Physiatrists.

BACKGROUND: Spine care is costly and subject to wide variability. Defining costs and patterns of care for different specialties is critical to improving value. OBJECTIVE: Determine costs, utilization, and differences therein for nonoperative and operative specialists in treating low back disorders. We hypothesized costs associated with nonoperative specialists would be lower. DESIGN: Retrospective cohort. SETTING: Medicare Limited Data Set (5% sample), 2011 to 2014. PARTICIPANTS: A total of 170 011 patients saw a primary care provider for a low back disorder between 1 July 2011, and 1 January 2013. Excluding those seen for a low back disorder in the preceding 6 months, final cohorts totaled 11 829 patients subsequently evaluated by a physiatrist (specialist in physical medicine and rehabilitation; 3183 patients) or surgeon (orthopedic or neurosurgeon; 8646 patients) within the following 6 months. MAIN OUTCOME MEASURES: Total Medicare expenditures, spine-specific costs, spine surgical rates over 24 months. RESULTS: Cohorts had comparable demographics, initial diagnoses, and baseline mean per-member per-month (PMPM) total spending. Mean 2-year spine-specific spending was $3978 for the physiatrist cohort and $7387 for the surgeon cohort. Comparatively, the physiatrist cohort had lower total mean 2-year spine-specific spending (-$3409; 95% confidence interval [CI] -$3824 to -$2994), mean PMPM total spending (-$122/mo; CI -$184 to -$60), and surgical rate (7.8% vs. 18.9%, risk ratio [RR] = 0.41; CI 0.36-0.47). Surgery predominantly drove cost differential. Mean PMPM total spending for both cohorts remained elevated at 24 months compared to baseline mean spending (physiatrist: +$293; CI $447 to $138; surgeon: +$325; CI $425 to $225). CONCLUSIONS: Following a new episode of a low back disorder, substantial costs were seen for those subsequently evaluated by a physiatrist or surgeon. Costs were considerably lower for those first seen by a physiatrist. Patients in both cohorts displayed long-term increases in health care costs. Our data suggest that early engagement in nonoperative care, when appropriate, may improve value.

Radiation and Hyperthermia Combination Therapy for Recalcitrant Verruca Vulgaris.

A 47-year-old white woman presented to our clinic complaining of recalcitrant warts on her trunk and extremities. She had an extensive past medical history including immunodeficiency of unknown origin, pulmonary hypertension, rheumatoid arthritis, and systemic lupus erythematosus, for which she was being treated with chronic immunosuppressive therapy with methylprednisolone and belimumab. The patient had previously failed treatments at an outside facility with liquid nitrogen, trichloroacetic acid, topical cidofovir, imiquimod, topical 5-fluorouracil, intralesional candida antigen, pulsed-dye laser (Vbeam Perfecta), surgical excision, and photodynamic therapy. (SKINmed. 2019;17:68-71).

The Circuitry of Dopamine System Regulation and its Disruption in Schizophrenia: Insights Into Treatment and Prevention.

Despite evidence for a role of the dopamine system in the pathophysiology of schizophrenia, there has not been substantial evidence that this disorder originates from a pathological change within the dopamine system itself. Current data from human imaging studies and preclinical investigations instead point to a disruption in afferent regulation of the dopamine system, with a focus on the hippocampus. We found that the hippocampus in the methylazoxymethanol acetate (MAM) rodent developmental disruption model of schizophrenia is hyperactive and dysrhythmic, possibly due to loss of parvalbumin interneurons, leading to a hyperresponsive dopamine system. Whereas current therapeutic approaches target dopamine receptor blockade, treatment at the site of pathology may be a more effective therapeutic avenue. This model also provided insights into potential means for prevention of schizophrenia. Specifically, given that stress is a risk factor in schizophrenia, and that stress can damage hippocampal parvalbumin interneurons, we tested whether alleviating stress early in life can effectively circumvent transition to schizophrenia-like states. Administering diazepam prepubertally at an antianxiety dose in MAM rats was effective at preventing the emergence of the hyperdopaminergic state in the adult. Moreover, multiple stressors applied to normal rats at the same time point resulted in pathology similar to the MAM rat. These data suggest that a genetic predisposition leading to stress hyper-responsivity, or exposure to substantial stressors, could be a primary factor leading to the emergence of schizophrenia later in life, and furthermore treating stress at a critical period may be effective in circumventing this transition.